Compactin and mevinolin are naturally-occurring compounds that are exceedingly effective competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase). Since this enzyme controls an important step in cholesterol biosynthesis, compounds that reversibly repress its activity are of potential utility as hypocholesterolemic drugs. Recently it has been found that inhibition of HMG CoA reductase also causes reversible cessation of DNA synthesis during the S phase in synchronized cell cultures. The cause of this inhibition of DNA synthesis has been traced to the inability of the cell to manufacture the "unusual" base N6 - (Delta2-isopentenyl) adenosine, an essential component of certain transfer RNA molecules. This discovery raises the exciting possibility that compactin and mevinolin, or their analogs, may be useful in controlling the growth of certain tumors. In this project total syntheses of compactin and mevinolin will be developed. Convergent syntheses that deliver the enantiomerically homogeneous natural products will be employed. The synthetic approach chosen will allow the ready preparation of analogs in which the upper "lactone portion" is excised from the lower "decalin portion" of the natural products. In this way it is hoped to ascertain the nature of binding of the inhibitors to the HMG CoA reductase active site. A series of ten specific analogs (compounds 68-71 and 76-81) will be synthesized and evaluated using liver microsomal HMG CoA reductase, purified HMG CoA reductase, and a multi-enzyme system from liver homogenate. If justified by these preliminary in vitro assays, in vivo evaluations will be carried out with selected analogs. Biochemical investigations will be carried out in collaboration with Professor George Popjak of the Department of Biochemistry of the UCLA School of Medicine.